DESCRIPTION (Applicant's Description): In recent years, epidemio logical reports have suggested a possible reduction in colon cancer risk among menopausal estrogen users. Despite this suggestive evidence, the collective results from twenty studies with information on this relationship are not in total agreement regarding this association; in particular, there is little consistency in the association with duration of hormone use. Because few previous studies were designed specifically to evaluate the role of menopausal hormones, details about usage patterns have generally been limited. Recent summaries of the health effects of hormone replacement therapy (HRT) have concluded that this issue remains unresolved and must be a high priority for future research. We propose to conduct a definitive study of the hypothesis that use of HRT reduces the risk of colon cancer. Consecutively diagnosed female colon cancer cases will be identified by the Cancer Surveillance Program, our population-based cancer registry in Los Angeles County (Core B) over 4.5 years. Controls will be individually matched to cases by age (+/-3 years), race, and neighborhood of residence. Complete lifetime histories of use of HRT will be collected. The 1368 case control pairs to be interviewed will allow us to answer questions regarding the association between colon cancer and any use of HRT and by dose, duration, latency of use, type of HRT regimens, and timing of HRT use after adjustment for possible confounding factors. Another objective of the proposed study is to evaluate the role of several other iatrogenic agents including oral contraceptives (OCs), calcium and vitamin D supplements, aspirin and NSAIDs, and laxatives in the etiology of colon cancer. Use of these agents may be correlated with use of HRT and some of these agents (e.g., OCs, calcium supplements) may influence risk of colon cancer via a similar mechanism as HRT. If there is an association between use of HRT and risk of colon cancer, the mechanism of action is not known. As we conduct this case-control study we propose to investigate concurrently if reduced CpG methylation of the estrogen receptor (ER) gene is associated with use of HRT. Our study will include the ER CpG methylation status of both tumor and normal adjacent mucosa; the latter is likely to be more informative than that of the resected tumor samples. To test this hypothesis, paraffin tumor blocks will be obtained on 208 colon cancer cases interviewed in the proposed case-control study. Distribution of percent ER methylation will be compared between 104 current users (minimum of one year of use) of estrogen replacement therapy (ERT) and 104 women who have never used HRT.